Glucocorticoids (GC) are still indispensable drugs in the treatment of multiple myeloma, an incurable blood cancer. These steroidal hormones trigger myeloma cell apoptosis by activating the glucocorticoid receptor (GR). Unfortunately, prolonged GC therapy is hampered by debilitating side effects that severely limit patient quality of life. A safer strategy that enhances the myeloma-killing capacity of GCs could allow for a lowering of the GC dose, such that patients would suffer less from these side effects. Pre-track work convincingly shows that bivalent ligands, consisting of a GR agonist coupled to a mineralocorticoid receptor (MR) antagonist, lead to more potent myeloma cell killing than the unlinked ligands combined. Therefore, the aim of my Ph.D. project is to unravel the underlying molecular mechanisms responsible for the enhanced anti-myeloma activity of bivalent ligands. In this EvdS-KOTK project, I will focus on the screening of bivalent ligand-induced anti-myeloma activity and the initial mechanistic characterization of these novel compounds by studying their impact on GR- and MR-based dimerization, as well as on the expression of a set of recently revealed co-controlled downstream targets within myeloma cells